1. Brain Res. 2004 Nov 26;1028(1):66-74.
In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced
neurotoxicity.
Farber NB, Heinkel C, Dribben WH, Nemmers B, Jiang X.
Department of Psychiatry, Washington University, Campus Box 8134 660 S. Euclid
Ave. St. Louis, MO, 63110-1093, USA.
[email protected]
Single doses of an NMDA antagonist cause an adult or a prepubertal form of
neurodegeneration, depending on the age of the animal. Single doses of ethanol
(EtOH) by blocking NMDA receptors produce apoptotic neurodegeneration in young
animals. This capability could account, in part, for the ability of EtOH to
produce the fetal alcohol syndrome. We investigated whether EtOH could produce
NMDA antagonist-induced neurotoxicity (NAN), a different neurotoxicity that is
seen only in adult animals. In spite of producing blood EtOH levels (30 to 600
mg/dl) known to block NMDA receptors, EtOH was unable to produce neurotoxicity in
the adult central nervous system (CNS). Moreover, EtOH in a dose-dependent
fashion (ED(50)=138 mg/dl) prevented the selective and powerful NMDA antagonist,
MK-801, from producing NAN in adult animals, suggesting that activity at another
site might be negating the neurotoxic effect of EtOH's inherent NMDA antagonistic
activity. Because GABA(A) agonism and non-NMDA glutamate antagonism, properties
which EtOH possesses, can prevent NAN, we proceeded to study whether GABA(A)
antagonists (or agents capable of reversing EtOH's GABAergic effects) and
non-NMDA agonists could reverse EtOH's protective effect. Bicuculline, Ro15-4513,
finasteride, kainic acid or AMPA, alone or in combination, did not significantly
reverse EtOH's protective effect. Given that EtOH has effects on a wide range of
ion channels and receptors, determining the precise mechanism of EtOH's
protective effect will take additional effort. The inability of EtOH to acutely
produce NAN in the adult CNS indicates that, in contrast to fetuses, brief
exposure of the adult CNS to EtOH is non-toxic for neurons.
PMID: 15518643 [PubMed - indexed for MEDLINE]